In the past we have demonstrated that the sensitivity of the subhuman mammalian iris to the miotic effect of a variety of cholinergic drugs is a dynamic phenomenon. Stimulus deprivation induced supersensitivity and overstimulation induced subsensitivity to the miotic effects of pilocarpine and carbachol were induced simply by varying the environmental lighting conditions, while complete insensitivity to the miotic effect of these drugs were shown to occur following chronic cholinesterase inhibitor treatment. Under the current grant we shall continue our investigation of the mechanism of control of cholinergic sensitivity using the mammalian iris as a model system. In a later phase of this project we will extend our studies to the control of the sensitivity of aqueous humor outflow mechanisms to the hypotensive effect of cholinergic drugs. We will investigate the possible role of prostaglandins and the cyclic nucleotide systems in these changes, and in the control of cholinergic sensitivity in general. We shall also examine the possibility that changes in cholinergic sensitivity are related to changes in receptor concentration. We shall use the isolated rat eye and the isolated cat iris sphincter preparation in vitro, and cats, rabbits and dogs for in vivo studies on the iris. Monkeys and normal and/or occular hypertensive beagle dogs will be used for in vivo studies on outflow faclity. These studies as well as studies on the effects of aging on the ability of the iris and the outflow mechanism to adjust to its normal neuronal input will ultimately be related to the elucidation of the etiology of glaucoma and to the development of better treatment methods for ocular hypertension.